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R EVI E W A R T IC L E The role of surgery in high-risk localised prostate cancer BJUI BJU INTERNATIONAL Vincent J. Gnanapragasam, Malcolm D. Mason*, Greg L. Shaw† and David E. Neal† Translational Prostate Cancer Group, Department of Oncology, Hutchison/MRC research centre and †Cambridge Research Institute, University of Cambridge, Cambridge, *Department of Oncology, Cardiff University, Velindre Hospital, Cardiff, UK Accepted for publication 10 June 2011 • The optimal management of high-risk localised prostate cancer is a major challenge for urologists and oncologists. It is clear that multimodal therapy including radical local treatment is needed in these men to achieve the best outcomes. • External beam radiotherapy (EBRT) is an essential component of therapy either as a primary or adjuvant treatment. However, the role of radical prostatectomy (RP) is more controversial. Both methods are currently valid therapy options. • There have been many individual studies of EBRT and RP in high-risk disease, but no good quality large prospective randomized trials. • In EBRT, combination with neoadjuvant plus long-term adjuvant androgen-deprivation therapy (ADT) has been conclusively shown to improve outcomes and is widely considered the standard of care. • However, the role of RP has achieved recent prominence with several important studies. Published data from prospective randomized trials in patients after RP have shown that in men with adverse pathological features at surgery, the addition of adjuvant RT improves biochemical-free and progression-free survival. • More recently, studies from large-volume centres comparing EBRT and RP have provided intriguing suggestions of better outcomes with RP as the primary treatment. • An important question therefore, is which of the two methods provides the best outcome in men with localised high-risk disease. Crucially, does the combination of RP and selective adjuvant EBRT provide clinically significant better outcomes compared with EBRT alone? • In this review we discuss the current evidence for the role of RP for high-risk localised prostate cancer and define the parameters and urgent need for a prospective trial to test the role of surgery for this group of patients. KEYWORDS INTRODUCTION 648 high-risk prostate cancer, radical prostatectomy, radical radiotherapy Men presenting with high-risk prostate cancer represent a significant proportion of patients treated by radical therapy either by external beam radiotherapy (EBRT) or radical prostatectomy (RP). In a review of 2380 men treated by EBRT or RP in the Memorial Sloan Kettering Cancer Centre in the USA, 17% were classed as having high-risk disease [1]. In the UK, contemporary surgical series from tertiary centres have identified that up to 13% of men will have high-grade disease [2]. In published UK and USA EBRT series, high-risk disease has been reported in 17–19% of men [3,4]. In our own institution a recent review identified 10% of men treated by RP and 16% of men treated by EBRT have high-risk disease ([5] and unpublished data). Men with high-risk disease have the highest incidence of treatment failure from radical therapy and disease progression and mortality [6,7]. These factors implicate high-risk prostate cancer as a key priority for improving prostate cancer outcomes. © BJU INTERNATIONAL © 2 0 11 T H E A U T H O R S 2 0 11 B J U I N T E R N A T I O N A L | 1 0 9 , 6 4 8 – 6 5 8 | doi:10.1111/j.1464-410X.2011.10596.x ROLE OF SURGERY IN HIGH-RISK LOCALISED PROSTATE CANCER The most widely accepted definition of high-risk disease is based on D’Amico’s risk classifications and is used in several national guidelines including those published by the AUA, European Association of Urology (EAU) and the UK National Institute for Health and Clinical Excellence [8–10]. These include a Gleason sum score of ≥8, or at least T2c clinical stage or a presenting PSA level of ≥20 ng/mL. High-risk disease is increasingly being defined by a high PSA level and high-grade disease as there is evidence of stage migration as a consequence of screening programmes or serendipitous PSA testing. In the pre-PSA era, organ-confined prostate cancer was found in ≈67% of men in the USA, while in 2000 this figure was up to 80% [8]. This pattern is also rapidly emerging in the UK and many men are presenting with more localised disease [11]. An increasingly relevant clinical question therefore is the role of surgery and RT in the treatment of high risk apparently localised disease at the point of presentation. RP is an effective treatment for men with localised low- and intermediate-risk prostate cancer. However, its role in the management of high-risk disease remains keenly debated. RP for high-risk localised prostate cancer is an attractive therapy option. It is the only method that provides definitive histopathological information as well as providing excellent loco-regional control. In addition, it allows for early detection of treatment failure when the PSA level fails to become undetectable or starts to rise. RP for localised high-risk disease in expert hands offers a high probability of delivering long-term control without the need for prolonged adjuvant systemic therapy. In men who do need additional therapy, adjuvant EBRT has been shown to provide an excellent chance of long-term control [12]. However, surgery does carry risks of mortality and morbidity as well as troublesome side-effects. Wide non-nerve © sparing dissections, and extended lymph node (LN) removal can also add to the surgical morbidity and complications. The important question therefore is whether surgery offers a benefit over primary EBRT for this group of men. In this review we discuss the evidence for surgery in localised prostate cancer as a primary therapy for high-risk disease and define the need and issues for a randomized trial comparing RP with EBRT in this context. OUTCOMES OF RADIOTHERAPY (RT) FOR HIGH-RISK PROSTATE CANCER after RT in particular seems advantageous; although whether all patients should be on long-term ADT, and for how long, is an area of current debate [24–26]. Currently, both the AUA and EAU prostate cancer guidelines advocate RT with neoadjuvant and adjuvant ADT for at least 2 years [8,9]. An on-going uncertainty until recently has been the relative contribution of EBRT and ADT in achieving the results in RT trials. The recent Scandinavian Prostate Cancer Group (SPCG)-7 and National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) PR3/ MRC PR-07 studies have now shown that it is the addition of RT to ADT that confers the best survival advantage [27,28]. Radical RT is currently the most common Most EBRT trials have been composed of treatment offered for men with high-risk mixed cohorts with a relative preponderance prostate cancer [6,13]. In locally advanced of men with locally advanced disease. The disease it is considered the standard of care [9]. There is clear evidence that EBRT combined with ‘Radical RT is currently the most common neoadjuvant and treatment offered for men with high-risk adjuvant androgenprostate cancer’ deprivation therapy (ADT) is superior to RT alone [14–16]. There have been reports of specific results in organ-confined tumours are less well defined, as few studies have 5- and 10-year biochemical-free outcomes reported outcomes solely in localised of up to 84% and 74.1%, respectively [17–21]. Bolla et al. [22] in 2010 reported on disease. D’Amico et al. [17] in 2000 reported on a retrospective analysis of 1586 men the 10-year follow-up of a randomized with clinically localised disease (T1c–T2c) study (n = 415) comparing EBRT or EBRT treated with EBRT or EBRT with ADT. The with 3 years of ADT in men with high-grade study groups were stratified by risk criteria. T1–2 disease or T3–4 of any grade. The That study identified that while outcomes 10-year disease-specific mortality was 30% were similar in men with low-risk disease, in the RT group alone compared with only those with intermediate- and high-risk 10% in the combined therapy group. Similar organ-confined disease had better 5-year benefits were also seen in overall survival biochemical relapse outcomes after (OS) rates. The Radiation Therapy Oncology Group (RTOG)-8610 trial reported on 10-year combined EBRT and ADT. In a follow on randomized study, the same authors outcomes in 2008 comparing EBRT with reported on outcomes from 206 men who EBRT and neoadjuvant ADT [23]. In that were treated with either EBRT or EBRT with study the combined treatment group had 6 months of ADT. At a median of 4.5 years shown improvements in all parameters of follow-up, the combined treatment group disease-specific mortality, distant metastasis had better outcomes compared with the and biochemical failure rates. Adjuvant ADT 2 0 11 T H E A U T H O R S BJU INTERNATIONAL © 2 0 11 B J U I N T E R N A T I O N A L 649 GNANAPRAGASAM ET AL. RT-alone group for freedom from salvage ADT and prostate cancer-specific mortality (82% vs 57% and 88% vs 78% respectively) [18]. More recently, Heymann et al. [19] in 2007 reported comparable results using a 9-month course of ADT in men with intermediate- or high-risk localised disease. These results and that of studies in locally advanced disease provide a rationale for EBRT as a primary therapy for localised disease in the absence of randomized comparisons with other radical local treatments. Moreover, the benefits of this combined approach seem to be most apparent in men with high-risk disease. Despite good results from EBRT a significant minority of men will develop disease progression. A key problem in EBRT failure is the lack of effective second-line local therapy. Local salvage therapies ‘Despite good results from EBRT a such as surgery, high-intensity significant minority of men will develop focused ultrasound disease progression’ and cryotherapy all carry significant risks of morbidity and complications, with most studies reporting 5-year biochemical relapse-free survivals of ≈50% [29,30]. Thus, when EBRT fails there are few proven effective local therapy options and many men are managed primarily by long-term ADT. OUTCOMES OF RP FOR HIGH-RISK LOCALISED PROSTATE CANCER Surgical case series reporting on outcomes for high-risk disease have included men with high PSA levels, high Gleason grades and advanced stage or combinations of these risk factors. These studies have been well reviewed elsewhere [31–33]. Good outcomes have been reported from several different centres. In a series of 175 high-risk cancers from the John Hopkins Institute in the USA, Loeb et al. [34] reported a 10-year ADT-free rate of 71% and a 92% cancerspecific survival (CSS) rate. Similar results were reported in Germany by Spahn et al. [35]; in a series of 375 men with high-risk disease treated by RP and stage-dependent adjuvant ADT, the 5- and 10-year CSS was 91.3% and 87.2% respectively. Koupparis et al [36] reported on 299 men with high-risk disease treated at the Vancouver Prostate Centre, Canada. At a median of 4.7 650 years follow-up, 70% of men were free of biochemical relapse and the disease-specific survival (DSS) was 99%. Hsu et al. [37] reviewed outcomes of 200 men with initial clinical stage T3a disease who were treated by RP. At 10 years the progression-free survival (PFS), DSS and OS were 85.4%, 91.6% and 77%, respectively. Positive margins and high tumour volume were important indicators of a poor outcome. Importantly, one in five tumours were pathologically down-staged to pT2 at the time of surgery. It is highly likely that similar down-staging would be contained within EBRT series (although conversely it may be balanced by T2 cases that are upstaged). Ploussard et al. [38] reported on a cohort of 110 men with high-risk disease managed by laparoscopic RP. The median follow-up was relatively short at just over 36 months and key determinants of relapse were adverse tumour stage (extracapsular extension/ seminal vesical involvement) and positive margins. In men who had pathological organ-confined cancer at surgery, none relapsed during follow-up. Defining outcomes in men with high-risk but clinically localised disease is more difficult. Studies which report on outcome from surgery in cohorts selected based on high Gleason grade, however, do provide important insights. Mian et al. [39] in 2002 reported on 188 men with Gleason score ≥8 disease and who did not receive any adjuvant therapy. Disease-free survival rates for the entire cohort were 71% and 55% at the 5- and 7-year follow-up. Patients with pathologically confined disease, however, did much better with disease-free survival rates of 84%. An earlier study by Oefelein et al. [40] also reported similar findings. In a series of high-grade tumours (n = 116), the 10-year DSS was 96% for stage ≤pT2c tumours but 78% for higher stage tumours. Another important aspect is tumour down-grading at surgery. Donohue et al. [41] reviewed 238 men with initial Gleason 8–10 disease on diagnostic biopsies. The incidence of tumour down-grading was 45% in the final RP specimen. Men who were down-graded also had significantly better outcomes in terms of biochemical recurrence-free survival (58% vs 27%). Again, it is highly likely that similar down-grading would be contained within an EBRT series. In this study an important finding was that tumours that were organ confined were the most likely to be © BJU INTERNATIONAL © 2 0 11 T H E A U T H O R S 2 0 11 B J U I N T E R N A T I O N A L ROLE OF SURGERY IN HIGH-RISK LOCALISED PROSTATE CANCER down-graded compared with locally advanced tumours. Similar findings were reported by Walz et al. [42] in 2011. In a multi-institutional cohort of high-grade cancers the lowest incidence of favourable pathology at RP (organ-confined, negative margin and Gleason <7) was in men with initial clinical T3 disease. This study also showed that men with only one high-risk feature had much better biochemical relapse-free outcomes compared with those with two or more features. These studies show that the outcomes from surgery are not uniform in men with high-risk disease. Importantly, many men may be downgraded and down-staged at the time of RP and this translates into more favourable outcomes. ADJUVANT RT AFTER RP An important aspect of RP in high-risk disease is the risk of adverse pathological features at surgery (more extensive disease or a positive margin). The role and benefit of adjuvant RT in this context has been clearly shown with the recent reporting of three seminal trials. In the European Organization for Research and Treatment of Cancer (EORTC)-22911 trial men with positive margins, seminal vesicle invasion or extracapsular extension were randomized to receive adjuvant RT or conservative management [43]. In this trial, men who had adjuvant RT had improved biochemical-free survival and PFS when compared with a conservatively managed control group (74% vs 52.6% and 87% vs 78%, respectively). The German Intergroup trial (ARO 96-02/AUO AP 09/95) randomized patients to receive adjuvant RT or observation only [44]. The study reported biochemical-free survival rates of 72% vs 54% in the treatment and non-treatment groups, respectively. The Southwest Oncology Group (SWOG) 8794 trial also reported very similar results [45]; at the 5-year follow-up biochemical relapse-free survival rates were 73% and 44% for the adjuvant and conservative treatment group, respectively. In addition, in the SWOG trial there was a significant increase in the recurrence-free survival interval as well as a reduced incidence of the need for hormonal therapy in an updated report on the study. These trials compared immediate adjuvant vs late salvage RT and at present the timing and optimal regime for adjuvant EBRT remains © investigated adjuvant therapy after RP keenly debated. The currently open [51–53]. Messing et al. [51] randomized men Radiotherapy and Androgen Deprivation in with positive LNs at RP to observation and Combination after Local Surgery (RADICALS) deferred treatment or immediate ADT. At a trial is actively seeking to address this median follow-up of 11 years there was a aspect [46]. These studies, however, do show significant improvement in OS and DSS as evidence that in men with pathologically well as PFS in the ADT group. In a separate unfavourable disease, the addition of study, Wirth et al. [53] also reported an adjuvant RT after surgery confers a significant benefit ‘ADT appears to confer a benefit on men in tumour control found to have LN-positive disease at surgery’ [12]. In men who present with high-risk but apparently localised disease, improvement in PFS with immediate ADT in however, many may not need adjuvant this group of patients. There was, however, therapy and will do well from surgery alone. no difference in OS or DSS in this study. Therefore currently, ADT appears to confer a benefit on men found to have LN-positive disease at surgery. Although untested it is ADT IN RP-TREATED HIGH-RISK possible that this benefit will also apply to PROSTATE CANCER men with local disease but who are at high risk of microscopic metastatic spread. There Numerous studies have reported on has been to date, no neoadjuvant plus neoadjuvant ADT trials in surgery, although none have specifically investigated men with adjuvant ADT surgical trial, which is the combination that has shown most efficacy high-risk disease. Aus et al. [47] at 7 years follow-up found no difference in DSS in 126 in men treated by RT for high-risk disease. men recruited into a randomized trial of surgery or surgery with 3 months of neoadjuvant ADT. Soloway et al. [48] NEOADJUVANT CHEMOTHERAPY IN RP recruited 282 men with ≤T2b disease in a TREATED HIGH-RISK PROSTATE CANCER multicentre study comparing RP and RP with 3 months of leuprolide. After 5 years of Early trials using different chemotherapy follow-up there was no difference in the regimens before surgery in high-risk men biochemical recurrence rate. Klotz et al. [49] have also failed to show convincing 2003 similarly reported no difference in OS evidence of long-term benefit. Clarke et al. in their study with up to 6 years follow-up. [54] reported on an early Phase II trial of Interestingly, the authors did report a neoadjuvant estramustine and etoposide significant benefit in biochemical diseasebefore RP in 16 men with locally advanced free survival in the subgroup of men with disease. Nine men achieved undetectable high-risk disease. Schulman et al. [50] PSA levels before surgery, but all had reported the outcomes from a European residual tumour in the resected specimen. prospective randomized study of Pettaway et al. [55] administered neoadjuvant ADT. Men who received ketoconazole and doxorubicin alternating neoadjuvant ADT had significant clinical and with vinblastine and estramustine together pathological down-staging as well as with ADT to 33 men with high-risk disease reduced positive margin rates. There was, before RP. Although all men achieved however, no difference seen in PSA undetectable PSA levels after surgery, the progression rates after surgery. In all these study endpoint of achieving a 20% pT0 rate studies a consistent finding was that ADT was not achieved. decreased positive margin rates but did not change biochemical survival or DSS. In 2004, docetaxel (Taxotere) became the Neoadjuvant ADT is therefore not currently first cytotoxic agent to show a survival recommended for patients undergoing benefit in men with metastatic castratesurgery for high-risk disease [8,9]. As these refractory prostate cancer [56,57]. The trials were not focused on high-risk men, survival benefit that taxanes exhibited in however, this is arguably based on absence advanced prostate cancer raised the of high quality evidence, rather than possibility that they may be effective in men convincing proof of absence of effect. There with lower disease burdens. Several studies are few randomized trials that have have explored the use of taxanes combined 2 0 11 T H E A U T H O R S BJU INTERNATIONAL © 2 0 11 B J U I N T E R N A T I O N A L 651 GNANAPRAGASAM ET AL. with RP. Dreicer et al. [58] trialled the use of six cycles of docetaxel before RP. In their initial report, 79% of men experienced a fall in PSA level after chemotherapy. In a follow-up paper published in 2007, only 43% of the study cohort was disease free at a median follow-up of 49.5 months [59]. A parallel immunohistochemical study in the ex vivo prostate failed to find any significant biological changes associated with therapy. A separate study using single agent docetaxel reported early findings in 2005 [60]. In that study the PSA level fell by 50% in half the cohort with chemotherapy and interval MRI showed a 25% reduction in tumour size in 89% of patients. In all, 16 men completed the regime but only seven of these had an undetectable PSA level at a mean follow-up of 26 months. Garzotto et al. [61] reported a trial of mitoxantrone and docetaxel given over 16 weeks before RP. Here a PSA level reduction was seen in 95% of men as well as a higher than ‘numerous studies of neoadjuvant chemotherapy expected negative surgical margin and indeed ADT have therefore so far failed to rate. The data was suggest that they have a convincing role in too immature to comment on improving outcomes from RP’ biochemical or survival outcomes. More recently Vuky et al. [62] in 2009 conducted a trial of docetaxel and gefitinib for 2 months before RP in 31 men with high-risk prostate cancer. In this study no complete pathological responses were seen although the combination was well tolerated. Docetaxel has also been evaluated combined with ADT. One of the earliest combination trials involved chemo-hormonal therapy and was reported by Prayer-Galetti et al. [63] in 2006. In this study, LHRH analogues were used in addition to estramustine and docetaxel in 21 men. Only 42% of men remained disease free at a mean follow-up of 4 years. A more aggressive regime was used by Konety et al. [64] with men with PSA levels of >20 ng/mL or T3–4 disease receiving ADT in conjunction with four cycles of paclitaxel, carboplatin and estramustine. At a median follow-up of 29 months, however, 55% of men had developed biochemical relapse. The current largest study investigating dual neoadjuvant chemotherapy is being conducted by the Cancer and Leukemia Group B group (90203) [65]. The study intends to randomize 652 to either RP alone vs LHRH analogue plus six cycles of docetaxel before RP. The intention is to accrue >700 high-risk men with the primary study endpoint to decrease 5-year recurrence rates. No interim results from this study have so far been published. In all these studies a common thread is a lack of complete responders at the time of surgery. Furthermore, in medium-term analysis chemotherapy whether alone or combined with ADT has not been shown to improve biochemical-free recurrence. Evidence from the numerous studies of neoadjuvant chemotherapy and indeed ADT have therefore so far failed to suggest that they have a convincing role in improving outcomes from RP and cannot currently be recommended in standard practice. COMPARISONS BETWEEN RP AND EBRT OUTCOMES FOR HIGH-RISK PROSTATE CANCER There are no good quality data that has directly compared RP and EBRT for high-risk prostate cancer and none that has focused on clinically organ-confined disease. The primary sources of comparisons have been from observational studies and casematched series. Abdollah et al. [66] in 2010 reviewed the comparative treatment outcomes of 404 604 USA men with clinically localised prostate cancer in a retrospective observational study. In the whole cohort, the disease-specific mortality was lowest in the men treated by RP (3.6%) compared with either EBRT (6.5%) or observation (10.8%). When stratified by risk category, men aged <69 years with high-risk disease also did best when treated by RP. However, in men aged >70 years both EBRT and RP had equivalent outcomes. In another observational study involving the Cancer of the Prostate Strategic Urologic Research Endeavor (CaPSURE) registry, Cooperberg et al. [67] compared the risk adjustedmortality outcomes in 7538 men treated by RP, EBRT or ADT. In that study there was a significant survival benefit in men treated by RP compared with either EBRT or ADT. Zelefsky et al. [1] published metastatic progression outcomes comparing 2380 men treated by either EBRT or RP and using competing risk regression analysis. Men in the RP group had pelvic LN dissection (PLND) and only a small percentage (6%) received adjuvant or salvage adjuvant EBRT. In the EBRT group half the cohort received © BJU INTERNATIONAL © 2 0 11 T H E A U T H O R S 2 0 11 B J U I N T E R N A T I O N A L ROLE OF SURGERY IN HIGH-RISK LOCALISED PROSTATE CANCER neoadjuvant and concurrent ADT. At a median of 8 years follow-up, RP was associated with a lower risk of progression to metastasis and prostate cancer-specific mortality. Crucially, the difference in rates of metastatic progression was most noticeable in men with high-risk disease (7.8% difference between the groups). In a study by Tewari et al. [68] in 2007, 453 men with Gleason 8 disease were treated by observation, EBRT or RP and followed for a median of >50 months. In that study the risk of cancer-specific death was 13.4% in RP group, 16.8% RT group and 43% with conservative treatment. Boorjian et al. [69] undertook a retrospective review focusing on high-risk men from the Mayo clinic treated by either RP or EBRT. At a median follow-up of 10 years for RP (n = 1238) and 6 years for EBRT plus ADT (n = 609), the 10-year CSS rates were identical at 92%. There was also no difference in the rates of disease progression or disease-specific mortality when comparing the two treatments. The only finding was that men who had RP had better OS rates (77%) compared with men treated by EBRT and ADT (62%) or EBRT alone (52%). These retrospective studies while very informative, suffer from the common shortfall of being non-randomized and involving different patient populations with the confounding influence of different treatment regimens (e.g. RT doses, adjuvant or neoadjuvant hormones). Nevertheless, these studies strongly justify further investigation to determine whether these differences are due to the superiority of surgery, or to case selection. The only published prospective randomized trial comparing RP and EBRT is a multicentre study conducted across five sites in Japan published in 2006 [70]. The study involved 95 patients treated for T2b–3N0M0 disease. All patients had 8 weeks of neoadjuvant diethylstilboestrol (300 mg) taken once daily before randomization. RP patients (n = 46) had concurrent PLND, with RT patients (n = 49) treated with 40–50 Gy to the pelvis followed by a 20 Gy boost to the prostate. The two groups were matched for patient and disease criteria. The median follow-up was 102 months. Here there was no significant difference between biochemical relapse, clinical progression or DSS. Contemporary EBRT regimes and the few cases in this study, however, make any meaningful conclusions difficult to draw. © ROLE OF LN THERAPY IN HIGH-RISK PROSTATE CANCER The most accurate diagnostic and staging technique for pelvic LNs is the extended template dissection [71]. This involves removal of the LNs in the obturator fossa, along the external and internal iliac chains and along the common iliac vessels up to the crossing of the ureters. Data from surgical series have shown that the combination of RP and extended PLNDs can improve biochemical-free progression and potentially DSS [72,73]. There is also known to be a direct relationship between the number of LNs removed at surgery and PFS and CSS whether or not they harbour obvious metastatic disease [74,75]. In a recent study of 614 men by Schiavina et al. [76] in 2010, those who had ≥10 LNs removed had better biochemical relapse-free survival compared with those had fewer LNs removed. Masterson et al. [77] reported that in men without nodal involvement, the number of negative LNs removed was positively associated with freedom from biochemical relapse. The primary benefit of extended PLNDs is therefore most evident in men with intermediate- and high-risk disease [86,87]. It is therefore justifiable to consider that optimal surgical therapy for high-risk disease should include an extended PLND. Indeed this is currently recommended by the EAU guidelines for surgery in high-risk prostate cancer. In RT, pelvic LN irradiation was part of the treatment protocol in many landmark trials of high-risk prostate cancer [14,21,23]. In 2009, the RTOG genitourinary group published a consensus statement on the extent of pelvic LNs that should be treated in high-risk prostate cancer [88]. This recommends treatment to the distal common iliac, pre-sacral, external iliac, internal iliac and obturator fossa LNs and is a very comparable template to the surgical extended PLND. OPTIMAL DESIGN FOR A POTENTIAL COMPARATIVE RP AND EBRT TRIAL IN HIGH-RISK PROSTATE CANCER In the presence of two comparable therapies there is a clear need for a prospective randomized trial to assess which provides the better outcome. In high-risk disease this is most apparent in the management of localised high-risk disease particularly as surgical outcomes appear better in this context compared with locally advanced disease. Recent evidence also confirms that men who have adjuvant RT after surgery do better than with surgery alone in the Even in the presence of positive LNs, outcomes from RP are very encouraging. A review of 507 men with LN-positive disease had a 10-year DSS of 86% with 56% free of biochemical relapse [78]. Daneshmand et al. [79] reported an even longer follow-up of 235 men with positive LNs at RP. Recurrence-free survival was 65% at 10 years and 58% at 15 years. The incidence of ‘Even in the presence of positive LNs, outcomes positive LNs from RP are very encouraging’ increases with higher risk disease [71]. In men with Gleason 8 disease, 55–80% context of positive margins, seminal vesicle involvement and extracapsular invasion [12]. have been found to have positive LNs at EBRT is therefore clearly an essential surgery. By contrast, studies of low-risk modality in the management of high-risk prostate cancer have failed to show localised prostate cancer. The key question is convincing evidence of a benefit of PLND whether a policy of surgery with selective [80]. Using the D’Amico criteria definition adjuvant RT offers an advantage when of low-risk disease, the incidence of LN compared with EBRT plus ADT. In essence, involvement has been shown to be low in does surgery offer an incremental benefit men undergoing limited PLNDs [81–83]. for these men? Another important issue is Extended PLND in these men have yielded the role of ADT in conjunction with radical higher rates of detection although therapy. Evidence from EBRT studies commonly only between 3% to 10% [84,85]. suggests that men with high-risk organBecause of these low yields and the confined disease benefit most from a potential morbidity associated with PLND, combined EBRT and ADT approach. However, current guidelines do not recommend in surgery this issue remains an open extended PLNDs in men with low-risk question. There have been no focused prostate cancer undergoing RP. 2 0 11 T H E A U T H O R S BJU INTERNATIONAL © 2 0 11 B J U I N T E R N A T I O N A L 653 GNANAPRAGASAM ET AL. FIG. 1. Proposed format of a trial comparing RP and ERBT for men with high-risk localised prostate cancer and suitable for either treatment. SVI, seminal vesicle invasion; ECE, extracapsular extension; SMDT, Specialist Multi Disciplinary Team. High risk localised prostate cancer SMDT review Suitable for Radical Radiotherapy or Radical Surgery Equipoise counselling Randomisation Group 1 Radical Radiotherapy with neo-adjuvant and adjuvant AD therapy Group 2 Radical Prostatectomy Common assessment of health scores e.g. quality of life, urinary symptoms, sexual function, radiation toxicity Extended lymph node dissection Pelvic node irradiation Adjuvant radiotherapy based on positive margins/SVI/ECE Primary outcomes of improved disease free and overall survival studies in men with high-risk disease and no study that has used a combination of neoadjuvant plus adjuvant approach as is routine in EBRT regimes. A further important aspect is the role of LN therapy. There is good evidence in surgical studies that extended PLNDs are beneficial. In EBRT, LN therapy is increasingly being recognised as an important aspect of treatment. A trial soon to open in the UK, PIVOTAL (Prostate and pelvIs Versus prOsTate Alone treatment for Locally advanced prostate cancer), is seeking to address this issue and will randomize men between RT to prostate only and prostate with pelvic nodal intensity modulated RT in patients with locally advanced prostate cancer. However, in the context of a trial comparing RP and EBRT in high-risk disease, it is reasonable to consider nodal therapy as a standard for both methods. This should include an extended PLND in surgery and for parity, a comparable template for irradiation in the RT cohort. A potential trial proposal is outlined in Fig. 1. An important aspect is the comparative side-effects of each treatment regime for patients. A prospective trial will allow a unique opportunity for a comparison between the two methods with assessment of multiple domains including health-related quality of life, urinary symptoms, erectile function and radiation effects from the baseline, through therapy and in follow-up. 654 This would be an essential tool to define the potential toxicity of combined therapy relative to any oncological benefit. CONCLUSION Men with high-risk localised prostate cancers are at the highest risk of disease relapse regardless of the primary therapy. Multimodal therapy is crucial in these men either by RP and selective adjuvant EBRT or primary EBRT combined with ADT. There is no doubt that EBRT is an important method for these patients either as a primary or adjuvant therapy. However, RP offers an attractive opportunity for tumour excision either as definitive management (where there is tumour down-staging and down-grading at surgery) or as a first step in multimodal therapy. There are emerging indications in observational studies that RP may offer benefits over EBRT in DFS and OS. However, there is no good Level 1 evidence to support this notion and this is needed before RP can be considered as a preferred therapy for these patients. In this uncertainty there is a critical need for a well-designed randomized study comparing these two treatments in this group of patients. This should involve optimal delivery of both methods and parity for LN treatment. It is clear that recruitment to © BJU INTERNATIONAL © 2 0 11 T H E A U T H O R S 2 0 11 B J U I N T E R N A T I O N A L ROLE OF SURGERY IN HIGH-RISK LOCALISED PROSTATE CANCER such a trial will be challenging and will require large numbers. As a first stage it is likely that a feasibility study will be needed to address if patients might agree to randomization and indeed the best way to achieve equipoise and optimise recruitment. However, this will be the only way to answer the on-going debate on the role of RP in high-risk localised prostate cancer. In particular, should RP remain a therapeutic option or in fact be an essential component of optimal (multimodal) treatment for this group of patients. 7 8 9 CONFLICT OF INTEREST None declared. 10 REFERENCES 1 2 3 4 5 6 © Zelefsky MJ, Eastham JA, Cronin AM et al. Metastasis after radical prostatectomy or external beam radiotherapy for patients with clinically localized prostate cancer: a comparison of clinical cohorts adjusted for case mix. J Clin Oncol 2010; 28: 1508–13 Bott SR, Freeman AA, Stenning S, Cohen J, Parkinson MC. Radical prostatectomy: pathology findings in 1001 cases compared with other major series and over time. BJU Int 2005; 95: 34–9 Parker CC, Norman AR, Huddart RA, Horwich A, Dearnaley DP. Pretreatment nomogram for biochemical control after neoadjuvant androgen deprivation and radical radiotherapy for clinically localised prostate cancer. Br J Cancer 2002; 86: 686–91 Zagars GK, Ayala AG, von Eschenbach AC, Pollack A. The prognostic importance of Gleason grade in prostatic adenocarcinoma: a long-term follow-up study of 648 patients treated with radiation therapy. Int J Radiat Oncol Biol Phys 1995; 31: 237–45 Sharma NL, Papadopoulos A, Lee D et al. First 500 cases of robotic-assisted laparoscopic radical prostatectomy from a single UK centre: learning curves of two surgeons. BJU Int 2010; 108: 739–47 Meng MV, Elkin EP, Latini DM, Duchane J, Carroll PR. Treatment of patients with high risk localized prostate cancer: results from cancer of the 11 12 13 14 15 16 prostate strategic urological research endeavor (CaPSURE). J Urol 2005; 173: 1557–61 Garzotto M, Hung AY. Contemporary management of high-risk localized prostate cancer. Curr Urol Rep 2010; 11: 159–64 Thompson I, Thrasher JB, Aus G et al., AUA Prostate Cancer Clinical Guideline Update Panel. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol 2007; 177: 2106–31 Heidenreich A, Aus G, Bolla M et al., European Association of Urology. EAU guidelines on prostate cancer. Eur Urol 2008; 53: 68–80 National Institute for Health and Clinical Excellence. CG58 Prostate cancer: full guideline. Available at: http://guidance.nice.org.uk/CG58/ Guidance/pdf/English. Accessed July 2011 Hussain S, Gunnell D, Donovan J et al. Secular trends in prostate cancer mortality, incidence and treatment: England and Wales, 1975–2004. BJU Int 2008; 101: 547–55 Morgan SC, Dearnaley DP. Additional therapy for high-risk prostate cancer treated with surgery: what is the evidence? Expert Rev Anticancer Ther 2009; 9: 939–51 Cooperberg MR, Cowan J, Broering JM, Carroll PR. High risk prostate cancer in the United States, 1990–2007. World J Urol 2008; 26: 211–8 Bolla M, Collette L, Blank L et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet 2002; 360: 103–6 Pilepich MV, Winter K, John MJ et al. Phase III radiation therapy oncology group (RTOG) trial 86-10 of androgen deprivation adjuvant to definitive radiotherapy in locally advanced carcinoma of the prostate. Int J Radiation Onc Biol Physics 2001; 50: 1243–52 Hanks GE, Pajak TF, Porter A et al., Radiation Therapy Oncology Group. Phase III trial of long-term adjuvant androgen deprivation after neoadjuvant hormonal cytoreduction and radiotherapy in locally advanced carcinoma of the prostate: the Radiation 17 18 19 20 21 22 23 24 25 Therapy Oncology Group Protocol 92-02. J Clin Oncol 2003; 21: 3972–8 D’Amico AV, Schultz D, Loffredo M et al. Biochemical outcome following external beam radiation therapy with or without androgen suppression therapy for clinically localized prostate cancer. JAMA 2000; 284: 1280–3 D’Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-month androgen suppression plus radiation therapy vs radiation therapy alone for patients with clinically localized prostate cancer: a randomized controlled trial. JAMA 2004; 292: 821–7 Heymann JJ, Benson MC, O’Toole KM et al. Phase II study of neoadjuvant androgen deprivation followed by external-beam radiotherapy with 9 months of androgen deprivation for intermediate- to high-risk localized prostate cancer. J Clin Oncol 2007; 25: 77–84 Pilepich MV, Caplan R, Byhardt RW et al. Phase III trial of androgen suppression using goserelin in unfavorable-prognosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group Protocol 85-31. J Clin Oncol 1997; 15: 1013–21 Pilepich MV, Winter K, Lawton CA et al. Androgen suppression adjuvant to definitive radiotherapy in prostate carcinoma–long-term results of phase III RTOG 85-31. Int J Radiat Oncol Biol Phys 2005; 61: 1285–90 Bolla M, Van Tienhoven G, Warde P et al. External irradiation with or without long-term androgen suppression for prostate cancer with high metastatic risk: 10-year results of an EORTC randomised study. Lancet Oncol 2010; 11: 1066–73 Roach M 3rd, Bae K, Speight J et al. Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: long-term results of RTOG 8610. J Clin Oncol 2008; 26: 585–91 Bolla M, de Reijke TM, Van Tienhoven G et al., EORTC Radiation Oncology Group and Genito-Urinary Tract Cancer Group. Duration of androgen suppression in the treatment of prostate cancer. N Engl J Med 2009; 360: 2516–27 Horwitz EM, Bae K, Hanks GE et al. 2 0 11 T H E A U T H O R S BJU INTERNATIONAL © 2 0 11 B J U I N T E R N A T I O N A L 655 GNANAPRAGASAM ET AL. 26 27 28 29 30 31 32 33 34 35 Ten-year follow-up of radiation therapy oncology group protocol 92-02: a phase III trial of the duration of elective androgen deprivation in locally advanced prostate cancer. J Clin Oncol 2008; 26: 2497–504 D’Amico AV. Is long-term androgen suppression right for everyone with locally advanced prostate cancer? Lancet Oncol 2010; 11: 1016–7 Widmark A, Klepp O, Solberg A et al. Scandinavian Prostate Cancer Group Study 7; Swedish Association for Urological Oncology 3. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet 2009; 373: 301–8 Warde PR, Mason MD, Sydes MR et al. Intergroup randomized phase III study of androgen deprivation therapy (ADT) plus radiation therapy (RT) in locally advanced prostate cancer (CaP) (NCIC-CTG, SWOG, MRC-UK, INT: T94-0110; NCT00002633). NCIC CTG PR.3/MRC PRO7/SWOG JPR3 Investigators. Proc. ASCO 2010 Kimura M, Mouraviev V, Tsivian M, Mayes JM, Satoh T, Polascik TJ. Current salvage methods for recurrent prostate cancer after failure of primary radiotherapy. BJU Int 2010; 105: 191–201 Uchida T, Shoji S, Nakano M et al. High-intensity focused ultrasound as salvage therapy for patients with recurrent prostate cancer after external beam radiation, brachytherapy or proton therapy. BJU Int 2011; 107: 378–82 Grubb RL, Kibel AS. High-risk localized prostate cancer: role of radical prostatectomy. Curr Opin Urol 2010; 20: 204–10 Stratton KL, Chang SS. Locally advanced prostate cancer: the role of surgical management. BJU Int 2009; 104: 449–54 Yossepowitch O, Eastham JA. Role of radical prostatectomy in the treatment of high-risk prostate cancer. Curr Urol Rep 2008; 9: 203–10 Loeb S, Schaeffer EM, Trock BJ, Epstein JI, Humphreys EB, Walsh PC. What are the outcomes of radical prostatectomy for high-risk prostate cancer? Urology 2010; 76: 710–4 Spahn M, Weiss C, Bader P et al. Long-term outcome of patients with high-risk prostate cancer following 656 36 37 38 39 40 41 42 43 44 45 radical prostatectomy and stagedependent adjuvant androgen deprivation. Urol Int 2010; 84: 164–73 Koupparis AJ, Grummet JP, HurtadoColl A et al. Radical prostatectomy for high-risk clinically localized prostate cancer: a prospective single institution series. Can Urol Assoc J 2011; Mar 1 [Epub ahead of print] Hsu CY, Joniau S, Oyen R, Roskams T, Van Poppel H. Outcome of surgery for clinical unilateral T3a prostate cancer: a single-institution experience. Eur Urol 2007; 51: 121–8 Ploussard G, Salomon L, Allory Y et al. Pathological findings and prostatespecific antigen outcomes after laparoscopic radical prostatectomy for high-risk prostate cancer. BJU Int 2010; 106: 86–90 Mian BM, Troncoso P, Okihara K et al. Outcome of patients with Gleason score 8 or higher prostate cancer following radical prostatectomy alone. J Urol 2002; 167: 1675–80 Oefelein MG, Smith ND, Grayhack JT, Schaeffer AJ, McVary KT. Long-term results of radical retropubic prostatectomy in men with high grade carcinoma of the prostate. J Urol 1997; 158: 1460–5 Donohue JF, Bianco FJ Jr, Kuroiwa K et al. Poorly differentiated prostate cancer treated with radical prostatectomy: long-term outcome and incidence of pathological downgrading. J Urol 2006; 176: 991–5 Walz J, Joniau S, Chun FK et al. Pathological results and rates of treatment failure in high-risk prostate cancer patients after radical prostatectomy. BJU Int 2011; 107: 765–70 Bolla M, van Poppel H, Collette L et al., European Organization for Research and Treatment of Cancer. Postoperative radiotherapy after radical prostatectomy: a randomised controlled trial (EORTC trial 22911). Lancet 2005; 366: 572–8 Wiegel T, Bottke D, Steiner U et al. Phase III postoperative adjuvant radiotherapy after radical prostatectomy compared with radical prostatectomy alone in pT3 prostate cancer with postoperative undetectable prostatespecific antigen: ARO 96-02/AUO AP 09/95. J Clin Oncol 2009; 27: 2924–30 Thompson IM Jr, Tangen CM, Paradelo 46 47 48 49 50 51 52 53 54 J et al. Adjuvant radiotherapy for pathologically advanced prostate cancer: a randomized clinical trial. JAMA 2006; 296: 2329–35 Parker C, Clarke N, Logue J et al., RADICALS Trial Management Group. RADICALS (Radiotherapy and Androgen Deprivation in Combination after Local Surgery). Clin Oncol (R Coll Radiol) 2007; 19: 167–71 Aus G, Hugosson J, Abrahamsson PA et al. The risk of malignancy in the surgical margin at radical prostatectomy reduced almost three-fold in patients given neo-adjuvant hormone treatment. Eur Urol 1996; 29: 413–9 Soloway MS, Pareek K, Sharifi R et al., Lupron Depot Neoadjuvant Prostate Cancer Study G. Neoadjuvant androgen ablation before radical prostatectomy in cT2bNxMo prostate cancer: 5-year results. J Urol 2002; 167: 112–6 Klotz LH, Goldenberg SL, Jewett MA et al. Long-term followup of a randomized trial of 0 versus 3 months of neoadjuvant androgen ablation before radical prostatectomy. J Urol 2003; 170: 791–4 Schulman CC, Debruyne FM, Forster G, Selvaggi FP, Zlotta AR, Witjes WP. 4-Year follow-up results of a European prospective randomized study on neoadjuvant hormonal therapy prior to radical prostatectomy in T2-3N0M0 prostate cancer. European Study Group on Neoadjuvant Treatment of Prostate Cancer. Eur Urol 2000; 38: 706–13 Messing EM, Manola J, Yao J et al., Eastern Cooperative Oncology Group study EST 3886. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol 2006; 7: 472–9 McLeod DG, Iversen P, See WA, Morris T, Armstrong J, Wirth MP. Bicalutamide 150mg plus standard care vs standard care alone for early prostate cancer. BJU Int 2005; 97: 247–54 Wirth MP, Weissbach L, Marx FJ et al. Prospective randomized trial comparing flutamide as adjuvant treatment versus observation after radical prostatectomy for locally advanced, lymph nodenegative prostate cancer. Eur Urol 2004; 45: 267–70 Clark PE, Peereboom DM, Dreicer R, Levin HS, Clark SB, Klein EA. Phase II © BJU INTERNATIONAL © 2 0 11 T H E A U T H O R S 2 0 11 B J U I N T E R N A T I O N A L ROLE OF SURGERY IN HIGH-RISK LOCALISED PROSTATE CANCER 55 56 57 58 59 60 61 62 63 64 © trial of neoadjuvant estramustine and etoposide plus radical prostatectomy for locally advanced prostate cancer. Urology 2001; 57: 281–5 Pettaway CA, Pisters LL, Troncoso P et al. Neoadjuvant chemotherapy and hormonal therapy followed by radical prostatectomy: feasibility and preliminary results. J Clin Oncol 2000; 18: 1050–7 Tannock IF, de Wit R, Berry WR et al., TAX 327 Investigators. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med 2004; 351: 1502–12 Petrylak DP, Tangen CM, Hussain MH et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004; 351: 1513–20 Dreicer R, Magi-Galluzzi C, Zhou M et al. Phase II trial of neoadjuvant docetaxel before radical prostatectomy for locally advanced prostate cancer. Urology 2004; 63: 1138–42 Magi-Galluzzi C, Zhou M, Reuther AM, Dreicer R, Klein EA. Neoadjuvant docetaxel treatment for locally advanced prostate cancer: a clinicopathologic study. Cancer 2007; 110: 1248–54 Febbo PG, Richie JP, George DJ et al. Neoadjuvant docetaxel before radical prostatectomy in patients with high-risk localized prostate cancer. Clin Cancer Res 2005; 11: 5233–40 Garzotto M, Myrthue A, Higano CS, Beer TM. Neoadjuvant mitoxantrone and docetaxel for high-risk localized prostate cancer. Urol Oncol 2006; 24: 254–9 Vuky J, Porter C, Isacson C et al. Phase II trial of neoadjuvant docetaxel and gefitinib followed by radical prostatectomy in patients with high-risk, locally advanced prostate cancer. Cancer 2009; 115: 784–91 Prayer-Galetti T, Sacco E, Pagano F et al. Long-term follow-up of a neoadjuvant chemohormonal taxanebased phase II trial before radical prostatectomy in patients with non-metastatic high-risk prostate cancer. BJU Int 2007; 100: 274–80 Konety BR, Eastham JA, Reuter VE et al. Feasibility of radical prostatectomy after neoadjuvant chemohormonal therapy for patients with high risk or locally advanced prostate cancer: results 65 66 67 68 69 70 71 72 73 of a phase I/II study. J Urol 2004; 171: 709–13 Eastham JA, Kelly WK, Grossfeld GD, Small EJ, Cancer and Leukemia Group B. Cancer and Leukemia Group B. CALGB) 90203: a randomized phase 3 study of radical prostatectomy alone versus estramustine and docetaxel before radical prostatectomy for patients with high-risk localized disease. Urology 2003; 62 (Suppl. 1): 55–62 Abdollah F, Sun M, Thuret R et al. A competing-risks analysis of survival after alternative treatment modalities for prostate cancer patients: 1988–2006. Eur Urol 2011; 59: 88–95 Cooperberg MR, Vickers AJ, Broering JM, Carroll PR. Comparative riskadjusted mortality outcomes after primary surgery, radiotherapy, or androgen-deprivation therapy for localized prostate cancer. Cancer 2010; 116: 5226–34 Tewari A, Divine G, Chang P et al. Long-term survival in men with high grade prostate cancer: a comparison between conservative treatment, radiation therapy and radical prostatectomy–a propensity scoring approach. J Urol 2007; 177: 911– 5 Boorjian SA, Karnes RJ, Viterbo R et al. Long-term survival after radical prostatectomy versus external beam radiotherapy for patients with high-risk prostate cancer. Cancer 2011; 117: 2883–91 Akakura K, Suzuki H, Ichikawa T et al. A randomized trial comparing radical prostatectomy plus endocrine therapy versus external beam radiotherapy plus endocrine therapy for locally advanced prostate cancer: results at median follow-up of 102 months. Jpn J Clin Oncol 2006; 36: 789–93 Heidenreich A, von Knobloch R, Varga Z. Extended pelvic lymphadenectomy in patients undergoing radical prostatectomy in prostate cancer: high incidence of lymph node metastases. J Urol 2001; 167: 1681–4 Joslyn SA, Konety BR. Impact of extent of lymphadenectomy on survival after radical prostatectomy for prostate cancer. Urology 2006; 68: 121–5 Bader P, Burkhard FC, Markwalder R, Studer UE. Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is 74 75 76 77 78 79 80 81 82 83 there a chance of cure? J Urol 2003; 169: 849–54 Heidenreich A, Ohlmann CH, Polyakov S. Anatomical extent of pelvic lymphadenectomy in patients undergoing radical prostatectomy. Eur Urol 2007; 52: 29–37 Jeschke S, Burkhard FC, Thurairaja R, Dhar N, Studer UE. Extended lymph node dissection for prostate cancer. Curr Urol Rep 2008; 9: 237–42 Schiavina R, Bertaccini A, Franceschelli A et al. The impact of the extent of lymph-node dissection on biochemical relapse after radical prostatectomy in node-negative patients. Anticancer Res 2010; 30: 2297–302 Masterson TA, Bianco FJ Jr, Vickers AJ et al. The association between total and positive lymph node counts, and disease progression in clinically localized prostate cancer. J Urol 2006; 175: 1320–5 Boorjian SA, Thompson RH, Siddiqui S et al. Long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. J Urol 2007; 178: 864–70 Daneshmand S, Quek ML, Stein JP et al. Prognosis of patients with lymph node positive prostate cancer following radical prostatectomy: long-term results. J Urol 2004; 172: 2252–5 Bhatta-Dhar N, Reuther AM, Zippe C, Klein EA. No difference in six-year biochemical failure rates with or without pelvic lymph node dissection during radical prostatectomy in low-risk patients with localized prostate cancer. Urology 2004; 63: 528–31 Makarov DV, Trock BJ, Humphreys EB et al. Updated nomogram to predict pathologic stage of prostate cancer given prostate-specific antigen level, clinical stage, and biopsy Gleason score (Partin tables) based on cases from 2000 to 2005. Urology 2007; 69: 1095–101 Narayan P, Fournier G, Gajendran V et al. Utility of preoperative serum prostate-specific antigen concentration and biopsy Gleason score in predicting risk of pelvic lymph node metastases in prostate cancer. Urology 1994; 44: 519–24 Bluestein DL, Bostwick DG, Bergstralh EJ, Oesterling JE. Eliminating the need for bilateral pelvic lymphadenectomy in 2 0 11 T H E A U T H O R S BJU INTERNATIONAL © 2 0 11 B J U I N T E R N A T I O N A L 657 GNANAPRAGASAM ET AL. select patients with prostate cancer. J Urol 1994; 151: 1315–20 84 Schuhmacher MC, Burkhard FC, Thalmann GN, Fleischmann A, Studer UE. Is pelvic lymph node dissection necessary in patients with a serum PSA <10 ng/mL undergoing radical prostatectomy for prostate cancer? Eur Urol 2006; 50: 272–9 85 Allaf ME, Palapattu GS, Trock BJ, Carter HB, Walsh PC. Anatomical extent of lymph node dissection: impact on men with clinically localized prostate cancer. J Urol 2004; 172: 1840–4 86 Hyndman ME, Mullins JK, Pavlovich CP. Pelvic node dissection in prostate cancer: extended, limited, or not at 658 all? Curr Opin Urol 2010; 20: 211– 7 87 Burkhard FC, Studer UE. The role of lymphadenectomy in high risk prostate cancer. World J Urol 2008; 26: 231–6 88 Lawton CA, Michalski J, El-Naqa I et al. RTOG GU Radiation oncology specialists reach consensus on pelvic lymph node volumes for high-risk prostate cancer. Int J Radiat Oncol Biol Phys 2009; 74: 383–7 Correspondence: Vincent J Gnanapragasam, Translational Prostate Cancer Group, Department of Oncology, Hutchison/MRC research centre, University of Cambridge, Hills Road, CB1 0XZ, Cambridge, UK. e-mail: [email protected] Abbreviations: (EB)RT, (external beam) radiotherapy; RP, radical prostatectomy; EAU, European Association of Urology; ADT, androgen-deprivation therapy; RTOG, Radiation Therapy Oncology Group; SPCG, Scandinavian Prostatic Cancer Group; CSS, cancer-specific survival; NCIC CTG, National Cancer Institute of Canada Clinical Trials Group; PFS, progression-free survival; DSS, disease-specific survival; OS, overall survival; EORTC, European Organization for Research and Treatment of Cancer; SWOG, the Southwest Oncology Group; RADICALS, Radiotherapy and Androgen Deprivation in Combination after Local Surgery; LN, lymph node; PLND, pelvic LN dissection. © BJU INTERNATIONAL © 2 0 11 T H E A U T H O R S 2 0 11 B J U I N T E R N A T I O N A L